Use of 5HT6 antagonists

ABSTRACT

A method of treating ADHD comprising administering a 5-HT 6  receptor antagonist according to formula (A) hereinbelow:                    
     wherein: 
     P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; 
     A is a single bond, a C 1-6 alkylene or a C 1-6 alkenylene group; 
     R 1  is halogen, C 1-6 alkyl optionally substituted by one or more halogen atoms, C 3-6 cycloalkyl, C 1-6 alkoxy, OCF 3 , hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkanoyl, nitro, amino, C 1-6 alkylamino or diC 1-6 alkylamino, cyano or R 1  is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; 
     n is 0, 1, 2, 3, 4, 5 or 6, 
     R 2  is hydrogen, C 1-6  alkyl or aryl C 1-6  alkyl; 
     R 3  is a group R 5  or together with R 5  forms a group (CH 2 ) 2 O or (CH 2 ) 3 O or R 3  is linked to R 2  to form a group (CH 2 ) 2  or (CH 2 ) 3 ; 
     R 4  is —X(CH 2 )p—R 6  where X is a single bond, CH 2 , O, NH or N—C 1-6  alkyl and p is 0 to 6 and R 6  is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R 6  is NR 7 R 8  where R 7  and R 8  are independently hydrogen, C 1-6  alkyl or arylC 1-6 alkyl; and 
     R 5  is hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkanoyl, nitro, trifluoromethyl, cyano or aryl.

This application is a 371 of PCT/EP99/06218, filed Aug. 25, 1997.

The present invention relates to the use of compounds known in the art as 5-HT₆ receptor antagonists in the treatment of hyperactivity disorders. More particularly the invention relates to the use of such compounds in the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

Attention Deficit Hyperactivity Disorder, which is also referred to in the literature as Attention Deficit Disorder/Hyperactivity Syndrome (ADD/HS), is a condition (or group of conditions) characterised by impulsiveness, distractibility, inappropriate behaviour in social situations and hyperactivity. ADD/HS is reported to have a prevalence of 3-5% (using DSM-IV criteria) in children (Diagnostic and Statistical Manual of Mental Disorders; 4th edition; American Psychiatric Association; 1994). It is believed that some 30-60% of such cases persist into adulthood (Zametkin A. J. and Borcherding B. G., Ann. Rev. Med. 1989, 40:447-51). This disorder can impair social function, learning and/or development and is therefore now recognised as a serious problem. It is further recognised that many children with ADHD go on to develop other comorbid conditions or social problems in adulthood.

In clinical terms ADHD is diagnosed if any one of the three main clinical features viz. inattention, over-activity and impulsiveness, persists in two or more situations, e.g. in both a home and school environment (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Washington, D.C.: American Psychiatric Association, 1994).

A particularly severe form of ADHD is termed Hyperkinetic Disorder. In Britain, this diagnosis is made only if all three of the main clinical features (inattention, over-activity and impulsiveness) have been present from an early age, persist in more than one situation (e.g. home and school) and impair function (The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organisation, 1993: 155-7). Reports indicate that 1 in 200 children suffer from hyperkinetic disorder (Taylor E., et al, The Epidemiology of Childhood Hyperactivity, Oxford University Press 1991: 93-113).

There are currently only a few therapeutic agents which are recognised as having efficacy in the treatment of childhood ADHD; at present the drugs of choice are dextroamphetamine, pemoline and in particular methylphenidate (Ritalin, ™). Antidepressants and antipsychotic medications such as risperidone may also be effective in some cases but these are not standard treatments. Although methylphenidate is probably the most widely used drug in the treatment of ADHD it suffers from a number of disadvantages: it is a controlled drug: is extensively metabolised and may cause confusion and hallucinations. Moreover, methylphenidate does not treat one of the three main clinical features of ADHD, namely inattentiveness, and in addition does not normalise ADHD children. There is therefore a need for a new treatment for ADHD and related disorders which demonstrate both an improved pharmacological profile and which do not have the associated disadvantages of currently known therapeutic agents.

The etiology of ADHD is still not well understood. However, there is evidence to suggest that ADHD is associated with abnormalities in the caudate (Ernst et al, Journal of Neuroscience, 1998, 18(15), 5901-5907.). It has now been found that certain compounds, known in the art as 5-HT₆ receptor antagonists, selectively increases activity of the nigrostriatal dopamine pathway and could therefore, specifically alleviate these abnormalities. The compounds of the present invention have additional effects on the central nervous system, namely, an increase in cognitive function. Consequently, such compounds have utility in the treatment of ADHD and related disorders.

The present invention therefore provides, in a first aspect, the use of a compound having 5-HT₆ receptor antagonist activity in the manufacture of a medicament for use in the treatment of ADHD.

A 5-HT₆ antagonist for use in this invention must be selective for 5-HT₆ receptors. Where used herein, this is intended to mean that the 5-HT₆ antagonist must have a greater than 10-fold selectivity for this receptor over other binding sites within the CNS, in particular, other 5-HT receptor sub-types and dopaminergic receptors. The most preferred compounds of this invention demonstrate greater than 100-fold selectivity for 5-HT₆ receptors. The selectivity of the compounds of this invention for 5-HT₆ receptors can be determined using binding assays methods which are well known to those skilled in the art.

Preferred compounds of this invention include those disclosed in patent applications WO 98/27081 (SmithKline Beecham p.l.c.) and WO 99/02502 (SmithKline Beecham p.l.c.). Compounds of this invention therefore include compounds of formula (A) and compounds of formula (B), which can be prepared according to methods described in WO 98/27081 and WO 99/02502 respectively.

wherein:

P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group;

R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more halogen atoms, C₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₆alkoxy, OCF₃, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl, nitro, amino, C₁₋₆alkylamino or diC₁₋₆alkylamino, cyano or R¹ is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

n i s 0, 1, 2, 3, 4, 5 or 6,

R² is hydrogen, C₁₋₆ alkyl or arylC₁₋₆ alkyl;

R³ is a group R⁵ or together with R⁵ forms a group (CH₂)₂O or (CH₂)₃O or R³ is linked to R² to form a group (CH₂)₂ or (CH₂)₃;

R⁴ is —X(CH₂)p—R⁶ where X is a single bond, CH₂, O, NH or N—C₁₋₆ alkyl and p is 0 to 6 and R⁶ is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R⁶ is NR⁷R⁸ where R⁷ and R⁸ are independently hydrogen, C₁₆ alkyl or aryl C₁₆ alkyl; and

R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, C₁₋₆alkanoyl, nitro, trifluoromethyl, cyano or aryl.

wherein:

P is phenyl, naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group;

B is SO₂;

R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more fluorine atoms, C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkanoyl C₁₋₆alkoxy, OCF₃, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, cyano, NR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen, C₁₋₆alkyl or optionally substituted phenyl, SR¹¹ where R¹¹ is as defined above or R¹ is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or R¹ together with a second R¹ substituent forms a group —O—CH₂—O—, OCH₂CH₂O—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—,

n is 0, 1, 2, 3, 4, 5 or 6;

R² is hydrogen, C₁₋₆alkyl, arylC₁₋₆ alkyl or together with group P form a 5 to 8 membered ring optionally substituted with one or more C₁₋₆alkyl groups;

R³ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkanoyl, C₁₋₆alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, trifluoromethyl, cyano or aryl or together with the group R⁵ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups;

R⁴ is —X(CH₂)p—R⁶ where X is a single bond, CH₂, O, NH or N-alkyl and p is 0 to 6 and R⁶ is an optionally substituted 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R⁶ is NR⁷R⁸ where R⁷ and R⁸ are independently hydrogen, C₁₋₆alkyl or arylC₁₋₆ alkyl; and

R⁵ is a group R³ or together with R³ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups.

Other compounds for use in this invention include those generically and specifically disclosed in patent application WO 97/27058 (SmithKline Beecham) and European patent applications EP 0815861 (Hoffman-la-Roche) and EP 0930302 (Hoffman-la-Roche).

Particularly preferred compounds of this invention include 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) amide (Example 83 in WO 98/27081), that is to say, the compound of formula (I)

and N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (Example 140 in WO 99/02502) that is to say, the compound of formula (II)

Compounds exhibiting 5-HT₆ receptor antagonist activity may form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric and methanesulphonic. Salts of 5-HT6 receptor antagonists therefore form an aspect of the invention. Suitably, a compound of formula (I) and (II) are used as the hydrochloride salt.

Certain compounds exhibiting 5-HT₆ antagonist activity are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention.

The present invention further provides a method of treatment of ADHD and other related disorders which comprises administering to a host in need thereof an effective amount of a 5-HT₆ receptor antagonist or a pharmaceutically acceptable salt thereof.

When used in therapy, the 5-HT₆ receptor antagonists are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.

A pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months. 

What is claimed is:
 1. A method of treating ADHD comprising administering a 5-HT₆ receptor antagonist of formula (A) hereinbelow to a subject having ADHD:

wherein: P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group; R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more halogen atoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy, OCF₃, hydroxy, C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkoxy substituted with hydroxy, C₁₋₆alkyloxy substituted with C₁₋₆alkoxy, C₁₋₆alkanoyl, nitro, amino, C₁₋₆alkylamino or diC₁₋₆alkylamino, cyano or R¹ is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; n is 0, 1, 2, 3, 4, 5 or 6, R² is hydrogen, C₁₋₆ alkyl or aryl C₁₋₆ alkyl; R³ is a group R⁵ or together with R⁵ forms a group (CH₂)₂O or (CH₂)₃O or R³ is linked to R² to form a group (CH₂)₂ or (CH₂)₃; R⁴ is —X(CH₂)p—R⁶ where X is a single bond, CH₂, O, NH or N—C₁₋₆ alkyl and p is 0 to 6 and R⁶ is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R⁶ is NR⁷R⁸ where R⁷ and R⁸ are independently hydrogen, C₁₋₆ alkyl or arylC₁₋₆alkyl; and R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, hydroxy, C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkoxy substituted with hydroxy, C₁₋₆alkyloxy substituted with C₁₋₆alkoxy, C₁₋₆alkanoyl, nitro, trifluoromethyl, cyano or aryl or a pharmaceutically acceptable salt thereof.
 2. A method according to claim 1 wherein the 5-HT₆ receptor antagonist is the compound of formula (I) (5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide) or a pharmaceutically acceptable salt thereof


3. A method of treating ADHD comprising administering a 5-HT₆ receptor antagonist of formula (B) or a pharmaceutically acceptable salt thereof to a subject having ADHD

wherein: P is phenyl, naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur; A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group; B is SO₂; R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more fluorine atoms, C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkanoyl, C₁₋₆alkoxy, OCF₃, hydroxy, C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkoxy substituted with hydroxy, C₁₋₆alkyloxy substituted with C₁₋₆alkoxy, nitro, cyano, NR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen, C₁₋₆alkyl or optionally substituted phenyl, SR¹¹ where R¹¹is as defined above or R¹ is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or R¹ together with a second R¹ substituent forms a group —O—CH₂—O—, OCH₂CH₂O—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—, n is 0, 1, 2, 3, 4, 5 or 6; R² is hydrogen, C₁₋₆alkyl, arylC₁₋₆alkyl or together with group P forms a 5 to 8 membered ring optionally substituted with one or more C₁₋₆alkyl groups; R³ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkanoyl, C₁₋₆alkoxy optionally substituted with one or more fluorine atoms, hydroxy, C₁₋₆alkyl substituted with hydroxy, C₁₋₆alkoxy substituted with hydroxy, C₁₋₆alkyloxy substituted with C₁₋₆alkoxy, nitro, trifluoromethyl, cyano or aryl or together with the group R⁵ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups; R⁴ is —X(CH₂)p—R⁶ where X is a single bond, CH₂, O, NH or N-alkyl and p is 0 to 6 and R⁶ is an optionally substituted 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R⁶ is NR⁷R⁸ where R⁷ and R⁸ are independently hydrogen, C₁₋₆ alkyl or arylC₁₋₆ alkyl; and R⁵ is a group R³ or together with R³ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups.
 4. A method according to claim 3 wherein the 5-HT₆ receptor antagonist is the compound of formula (II) (N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide) or a pharmaceutically acceptable salt thereof 